Universität zu Köln

Delle Vedove, Andrea, Storbeck, Markus, Heller, Raoul, Hoelker, Irmgard, Hebbar, Malavika, Shulda, Anju, Magnusson, Olafur, Cirak, Sebahattin, Girisha, Katta M., O'Driscoll, Mary, Loeys, Bart ORCID: 0000-0003-3703-9518 and Wirth, Brunhilde ORCID: 0000-0003-4051-5191 (2016). Biallelic Loss of Proprioception-Related PIEZO2 Causes Muscular Atrophy with Perinatal Respiratory Distress, Arthrogryposis, and Scoliosis. Am. J. Hum. Genet., 99 (5). S. 1206 - 1217. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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Abstract

We report ten individuals of four independent consanguineous families from Turkey, India, Libya, and Pakistan with a variable clinical phenotype that comprises arthrogryposis, spontaneously resolving respiratory insufficiency at birth, muscular atrophy predominantly of the distal lower limbs, scoliosis, and mild distal sensory involvement. Using whole-exome sequencing, SNPchip-based linkage analysis, DNA microarray, and Sanger sequencing, we identified three independent homozygous frameshift mutations and a homozygous deletion of two exons in PIEZO2 that segregated in all affected individuals of the respective family. The mutations are localized in the N-terminal and central region of the gene, leading to nonsense-mediated transcript decay and consequently to lack of PIEZO2 protein. In contrast, heterozygous gain-of-function missense mutations, mainly localized at the C terminus, cause dominant distal arthrogryposis 3 (DA3), distal arthrogryposis 5 (DA5), or Marden-Walker syndrome (MWKS), which encompass contractures of hands and feet, scoliosis, ophthalmoplegia, and ptosis. PIEZO2 encodes a mechanosensitive ion channel that plays a major role in light-touch mechanosensation and has recently been identified as the principal mechanotransduction channel for proprioception. Mice ubiquitously depleted of PIEZO2 are postnatally lethal. However, individuals lacking PIEZO2 develop a not life-threatening, slowly progressive disorder, which is likely due to loss of PIEZO2 protein in afferent neurons leading to disturbed proprioception causing aberrant muscle development and function. Here we report a recessively inherited PIEZO2-related disease and demonstrate that depending on the type of mutation and the mode of inheritance, PIEZO2 causes clinically distinguishable phenotypes.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Delle Vedove, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Storbeck, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Heller, Raoul UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoelker, Irmgard UNSPECIFIED UNSPECIFIED UNSPECIFIED Hebbar, Malavika UNSPECIFIED UNSPECIFIED UNSPECIFIED Shulda, Anju UNSPECIFIED UNSPECIFIED UNSPECIFIED Magnusson, Olafur UNSPECIFIED UNSPECIFIED UNSPECIFIED Cirak, Sebahattin UNSPECIFIED UNSPECIFIED UNSPECIFIED Girisha, Katta M. UNSPECIFIED UNSPECIFIED UNSPECIFIED O'Driscoll, Mary UNSPECIFIED UNSPECIFIED UNSPECIFIED Loeys, Bart UNSPECIFIED orcid.org/0000-0003-3703-9518 UNSPECIFIED Wirth, Brunhilde UNSPECIFIED orcid.org/0000-0003-4051-5191 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-255972
DOI:	10.1016/j.ajhg.2016.09.019
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	99
Number:	5
Page Range:	S. 1206 - 1217
Date:	2016
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MARDEN-WALKER-SYNDROME; DISTAL ARTHROGRYPOSIS; 5-SPLICE-SITE RECOGNITION; MUTATIONS; CHANNELS; MECHANOTRANSDUCTION; GENE; PHENOTYPES; MECHANISM; PROTEINS Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25597